One of the main objectives of the work carried out under NIH Grant AM11448 has been to investigate the genetic mechanism of x-ray induced lethal mutations at the albino locus of the mouse resulting in multiple enzyme deficiences and in ultra-structural defects of the endoplasmic reticulum. The 3 enzymes which were found to be deficient in 4 different mutant strains were glucose-6-phosphatase, tyrosine amino-transferase, and serine dehydratase. Although these enzymes occur in different compartments of the cell, they have in common a rapid perinatal development. These and other findings (e.g., the absence of a gene dosage effect in the heterozygotes) were difficult to reconcile with the idea that the mutations were due to alterations in the structural genes for the respective enzymes. As a working hypothesis, the mutations are ascribed to an alteration of a regulatory gene which controls the appearance of these enzymes at birth. A new albino mutation, lethal in intraline crosses, has been found to produce viable albino offspring in interline crosses with any of the 4 previously ivestigated mutant strains. Enzyme levels appear to be returned to normal in some of these crosses. Further work is contemplated in the following directions. (1) Protein synthesis. As previously reported, the albino mutants at birth show a decrease in serum proteins. This will be investigated by acrylamide gel electrophoresis of individual serum proteins and by in vivo pulse labelling of the proteins in liver and in plasma. For a more detailed study of the deficiency in protein synthesis, an in vitro system can be set up, prepared from the liver of mutant and normal mice. (2) Fusion of mutant mouse liver cells with functionally normal rat liver cells, combined with immunochemical methods to identify mouse and rat enzymes in the mouse-rat hepatocyte heterodaryon. (3) Kinetic studies of the membrane-bound glucose-6-phosphatase, with special reference to SH groups. Localization of the enzyme on acrylamide gels by labelling it with 32P. BIBLIOGRAPHIC REFERENCE: Helmreich, E.J.M., Zenner, H.P., Pfeuffer, T. and Cori, C.F.: Signal transfer from hormone receptor to adenylate cyclase, in "Current Topics in Cellular Regulation, vol. 10", B.L. Horecker and E.R. Stadtmen, Editors, Academic Press, N.Y., pp. 41-87 (1976).